New mixed cage dimers of 4-phenyl-1,4-dihydropyridine derivatives, useful as HIV-1 protease inhibiting anti-HIV agents which also modulate HIV resistance by inhibiting P-glycoprotein

摘要

Asymmetric mixed cage dimers (I) of 3,5-bis-(hydroxymethyl)-4-phenyl-1,4-dihydropyridines are new. Dihydropyridine dimers of formula (I) and their salts are new. R1>H or alkyl; R2alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl or arylcarbonyl; X : alkoxy, OH, alkoxymethyl, CH2OH, H or NH2. An independent claim is included for the preparation of (I). [Image] ACTIVITY : Anti-HIV. MECHANISM OF ACTION : HIV-1 protease inhibitor. The mixed cage dimer (Ia) of 1-benzyl-3,5-bis-(hydroxymethyl)-4-phenyl-1,4-dihydropyridine and 3,5-bis-(hydroxymethyl)-4-(4-methoxyphenyl)-1-(tert. butoxycarbonyl)-1,4-dihydropyridine had inhibition constant 600 nM for inhibition of HIV-1 protease and showed 30 times stronger P-glycoprotein inhibiting activity than verapamil at a concentration of 10 mu M in tests in cells expressing P-glycoprotein.